We propose to study the modulation of substrate supply for cholesterol synthesis by the recycling of mevalonate and by the utilization of ketone bodies. The recycling and and urinary excretion of mevalonate modulate the level of circulating substrate which in turn modulates peripheral cholesterol synthesis. The recycling of mevalonate occurs primarily in the kidney and is more active in female than in males. Conditions such as chronic kidney failure, aging, diabetes and alcoholism are potential inhibitors of mevalonate recycling and may lead to increased peripheral synthesis of cholesterol. This problem will be investigated in isolated perfused livers, kidneys, lungs and testes from male and female rats. Using these models, we shall investigate the influence of leucine or ethanol catabolism or mevalonate recycling. We shall also conduct experiments aimed at defining the compartmentation of the recycling. The plasma level and urinary excretion of mevalonate will be measured in normal humans and in patients suffering from hypercholesterolemia, obesity, diabetes, chronic kidney failure and alcoholism. We hope that these tests will become useful parameters of lipid profile. We have recently demonstrated that contrary to accepted knowledge, the liver reuses a large fraction of its ketone body production for lipid synthesis in particular for cholesterol synthesis. We plan to investigate in perfused livers the lipogenic capacity of ketone bodies as influenced by aging, diabetes and high fat feeding.